Effects of a novel angiotensin AT 1 receptor antagonist, HR720, on rats with myocardial infarction

Abstract

Cardiac remodeling after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of the present study was to assess the effects of chronic treatment with a novel angiotensin AT 1 receptor antagonist 2-butyl-4-(methylthio-)-1-[[2′[[[(propylamino)carbonyl]amino]sulfonyl](1,1′-biphenyl)-4-yl]methyl]-1 H-imidazole-5-carboxylate (HR720), on cardiac remodeling and left ventricular dysfunction in a rat model of large myocardial infarction. Rats were subjected to permanent ligation of the left coronary artery and were treated for six weeks with placebo or HR720 (3 mg/kg/day) initiated 24 h after surgery. Sham-operated rats served as normal controls. Mean arterial blood pressure, the maximum rate of rise of the left ventricular systolic pressure (d P/d t max), left ventricular end-diastolic pressure, left ventricular inner diameter and circumference, septal thickness, left ventricular collagen content and heart weight were measured at the end of the treatment. HR720 treatment versus placebo attenuated the cardiac hypertrophy (heart weight/body weight: 2.88±0.08 mg/g vs. 3.16±0.09 mg/g, P<0.05), reduced interstitial collagen content (3.47±0.28% vs. 5.25±0.45%, P<0.01), limited infarct size (33.0±3.0% vs. 41.5±2.3%, P<0.05), decreased left ventricular end-diastolic pressure (13.7±2.2 vs. 21.4±1.6 mm Hg, P<0.01) and improved d P/d t max (9000±430 vs. 6000±840 mm Hg/s, P<0.05). The present results demonstrate that chronic treatment with the angiotensin AT 1 receptor antagonist HR720 can limit infarct size, partially prevent cardiac hypertrophic remodeling and improve left ventricular function in rats with myocardial infarction.